Real-World Evidence in Cost-Effectiveness Analysis of Enhanced Influenza Vaccines in Adults ≥ 65 Years of Age: Literature Review and Expert Opinion

Influenza vaccination can benefit most populations, including adults ≥ 65 years of age, who are at greater risk of influenza-related complications. In many countries, enhanced vaccines, such as adjuvanted, high-dose, and recombinant trivalent/quadrivalent influenza vaccines (aTIV/aQIV, HD-TIV/HD-QIV, and QIVr, respectively), are recommended in older populations to provide higher immunogenicity and increased relative vaccine efficacy/effectiveness (rVE) than standard-dose vaccines. This review explores how efficacy and effectiveness data from randomized controlled trials and real-world evidence (RWE) are used in economic evaluations. Findings from published cost-effectiveness analyses (CEA) on enhanced influenza vaccines for older adults are summarized, and the assumptions and approaches used in these CEA are assessed alongside discussion of the importance of RWE in CEA. Results from many CEA showed that adjuvanted and high-dose enhanced vaccines were cost-effective compared with standard vaccines, and that differences in rVE estimates and acquisition price may drive differences in cost-effectiveness estimates between enhanced vaccines. Overall, RWE and CEA provide clinical and economic rationale for enhanced vaccine use in people ≥ 65 years of age, an at-risk population with substantial burden of disease. Countries that consider RWE when making vaccine recommendations have preferentially recommended aTIV/aQIV, as well as HD-TIV/HD-QIV and QIVr, to protect older individuals.


Supplemental Searches
The reference lists of retrieved primary studies, systematic reviews, and meta-analyses were searched to capture additional studies. Congress presentations that included CEA or cost-utility analysis (CUA; hereafter referred to simply as CEA for convenience) were included based on expert knowledge and ability to retrieve poster and oral presentations.

Included Studies
Identified papers describing CEA from any world region were prioritized for inclusion. Included papers regarded enhanced vaccines in populations ≥ 65 years of age (or >50 years of age in models regarding QIVr). To be included, studies reported multiple parameters from the following: model type, country setting, vaccine strategy, study perspective, time horizon, selected costs, currency, rVE and/or VE, discounting strategies, and use of uncertainty analyses. Included studies could use VE and rVE inputs generated from RCTs and/or RWE.
Publications identified via the search strings, published reference lists, and based on expert knowledge are captured in Tables 2 and 3. Systematic review methodologies were not used.

Comparison between CEA for Enhanced and Standard Vaccines
In many countries, CEA have estimated the economic value of enhanced vaccines for older populations. Thirty-one CEA comparing enhanced vaccines to standard-dose vaccines were analyzed, 17 comparing aTIV/aQIV with TIV/QIV (Table 2A) and 14 comparing HD-TIV/HD-QIV with TIV/QIV (Table 2B). Studies included static and dynamic designs, and perspectives included healthcare system, societal, and third-party payer. Most studies included probabilistic and/or deterministic sensitivity analyses. Time horizons varied from one influenza season or year, although some models took a multi-year or lifetime approach. Discounting ranged from 0-5% for outcomes and costs. Most studies had an industry sponsor.

Comparison between Enhanced Vaccines in CEA
CEA results were inconsistent when enhanced vaccines were compared with each other. Six studies compared aTIV/aQIV with HD-TIV/HD-QIV (mostly Seqirus-sponsored), ten studies compared HD-TIV/HD-QIV with aTIV/aQIV (mostly Sanofi-sponsored), and two studies compared QIVr with aQIV. Studies included static and dynamic designs, and perspectives ranged between healthcare system, societal, and third-party payer. Time horizons varied between one and multiple seasons. Discounting ranged from 0-5% for outcomes and costs. Most studies included deterministic and probabilistic sensitivity analyses. Findings remained robust across sensitivity analyses. Rate of hospitalization, rVE, and vaccine acquisition price were drivers of cost-effectiveness (CE) in many models (Table 3).
Two CEA studies of interest were identified for QIVr (Table 3C). The first estimated the effect of switching from QIV/aQIV to QIVr in two age cohorts (≥18 years of age and ≥65 years of age) in the Spanish population using a static decision tree model [104]. The study estimated that mortality, hospitalizations, general practitioner visits, and emergency room services would decrease by 12%, 13%, 11%, and 12%, respectively, should the switch from QIV/aQIV to QIVr be implemented [104]. The second study did not find QIVr costeffective compared with aQIV for individuals ≥ 65 years of age living in Spain. To achieve an incremental cost-effectiveness ratio (ICER) within the willingness-to-pay threshold, the rVE of QIVr versus aQIV would need to reach 34.1% [105].

Systematic Reviews of CEA
Further to primary CEA studies, several systematic reviews of CEA for enhanced vaccines in older adults have been published [31][32][33][34]. A systematic review of the costeffectiveness of HD-TIV in individuals ≥ 65 years of age identified that HD-TIV was either cost-effective or cost-saving across multiple analyses [33], and that the prevention of cardiorespiratory complications was a potential driver of economic benefits [33]. Many of the studies included in this systematic review were also included in our analysis (such as [65][66][67][68]101], which are included in Table 2B). A comprehensive review from Canada suggested that aTIV, HD-TIV, and QIV were cost-effective compared with TIV for individuals ≥ 65 years of age, but noted a lack of head-to-head comparisons between QIV, HD-TIV, and aTIV [31]. The authors suggested that future studies should include realworld evaluations, and that methodological, structural, and parameter uncertainty should be assessed in CEA [31]. Similarly, a systematic review of seasonal influenza vaccine economic evaluations in individuals ≥ 60 or ≥65 years of age from the European Union recommended linking economic evaluations to observational cohort studies, RCTs, or other long-term, prospective, controlled studies [32]. The authors pointed out the need for data over multiple seasons, owing to influenza virus mutations and the potential for vaccine mismatch [32]. Finally, a review of economic analyses of aTIV in older adults identified aTIV as cost-effective or cost-saving compared with no vaccination or non-adjuvanted vaccines [34].     * rVE values input into models may be inferred across vaccine families (i.e., researchers assumed equivalent VE between aTIV and aQIV; researchers assumed equivalent VE between HD-TIV and HD-QIV). aQIV, adjuvanted quadrivalent influenza vaccine; aTIV, adjuvanted trivalent influenza vaccine; CE, cost-effectiveness; CV, cardiovascular; DSA, deterministic sensitivity analysis; ED, emergency department; ER, emergency room; GP, general practitioner; HD-QIV, high-dose quadrivalent influenza vaccine; HD-TIV, high-dose trivalent influenza vaccine; ICER, incremental cost-effectiveness ratio; LCI, laboratory-confirmed influenza; NR, not reported; PERR, prior event rate ratio; PSA, probabilistic sensitivity analysis; QALY, quality-adjusted life year; QIV, quadrivalent influenza vaccine; QIVe, egg-based quadrivalent influenza vaccine; QIVr, recombinant quadrivalent influenza vaccine; RCT, randomized controlled trial; rVE, relative vaccine effectiveness; SEIR, susceptible, exposed, infected, and recovered; TIV, trivalent influenza vaccine; TIVe, egg-based trivalent influenza vaccine; VE, vaccine effectiveness.

Critical Assessment of CEA Inputs and Approaches
CEA is a robust process that involves a variety of inputs, including, but not limited to, price, effectiveness, and utility, which supports decision analysis and is amenable to sensitivity testing [115]. Many economic analyses are performed to a high standard in accordance with gold-standard reporting guidelines for CEA, such as Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 [116]. Selection of robust inputs is of critical importance to the usability of findings from CEA models.

Importance of RWE for Influenza
It is important for public health officials to closely monitor circulating virus strains and for annual influenza vaccines to be adjusted and assessed on a seasonal basis [7]. Although vaccinated individuals achieve a level of cross-protection during mismatched seasons, VE usually decreases during mismatched seasons [90], and other factors, such as prior exposure, timing of vaccination, and waning immunity, may affect VE. The ability to assess vaccine performance in real time over multiple seasons, including those characterized by antigenic mismatch [8], is of high value for influenza.
Whereas RCTs aim to answer a focused research question by minimizing bias and confounders through randomization, blinding, and patient selection criteria, observational studies better reflect real-world conditions and are more easily performed over multiple influenza seasons with different circulating strains. Studies of real-world data sources may evaluate larger, more diverse, and more representative study populations than RCTs, potentially leading to more generalizable and clinically relevant results [27,28]. RWE may be used more often for influenza vaccine recommendations than for other vaccines or decisions in other disease areas [117,118], owing to timeline, cost, ethical, and enrollment difficulties of conducting RCTs to evaluate influenza vaccines in older individuals [28,119]. However, RWE may be subject to bias and similar studies may return conflicting results. For example, as assessed by Gärtner et al., 2022, of the seven retrospective cohort studies included in a systematic review discussing RWE of enhanced vaccines for older adults, three were found to have serious risk of bias owing to 'inadequate control for important confounders', 'selection of reported outcome', and 'selection of participants', and four were at moderate risk of bias [11]. RCTs themselves may also be subject to selection and/or informational bias, and new ways of defining 'high-quality evidence' have been proposed [120].
Multiple tools are used to assess and describe the risk of bias in non-randomized studies, and these approaches are very important for assessing the quality of RWE. Metaanalyses and systematic reviews may assess the risk of bias between studies (e.g., using Egger's test to assess potential positive publication bias) or within studies (e.g., using the GRACE, Cochrane Risk of Bias, ROBINS-I, or AMSTAR 2 tools) to rank study design, conduct, and evidence against several parameters to determine an overall risk of bias for individual studies [11,92,121,122]. To support the transparent communication of findings, the structured template and reporting tool for real-world evidence (STaRT-RWE) provides guidance endorsed by the International Society of Pharmacoepidemiology and the Transparency Initiative [123]. STaRT-RWE aims to support researchers by setting clear reporting expectations, leading to reduced misinterpretation and improved validity assessment [123]. A review of RWE studies published using this template shows that STaRT-RWE has the potential to improve the reporting standards for RWE studies [124].
From a public health perspective, policymakers should understand epidemiological methods and have familiarity with seasonal influenza patterns to utilize RWE studies appropriately for decision-making. Confounding factors, such as comorbidities, health status, or previous history of vaccination, can alter estimates of effectiveness in studies without randomized designs [119]. In observational studies, different methods to identify and adjust for confounding factors can be used, including multivariate sensitivity analysis, restriction, matching, and stratification [119]. Early enhanced vaccine RWE studies in Italy, including Mannino et al., 2012, determined that aTIV reduces the risk of influenza-or pneumonia-related hospitalization by 25% compared with TIV in older adults [85]. This study used a prospective, observational design to capture evidence from multiple influenza seasons between 2006-2009, and stratification and statistical procedures to control for confounding, such as propensity-score-based multivariate analysis [85]. In this case, bias inherent in the non-randomized design may have diminished the impact of effectiveness findings (i.e., bias towards the null, as the authors suggest that their estimate may have under-reported the number of influenza-or pneumonia-related hospitalizations prevented by aTIV compared with TIV [85]. Bias towards the null arising from misclassification of outcomes has been mentioned in this and other studies of enhanced vaccines [85,125]. Use of real-world inputs in CEA is increasing as regulators and payers recognize the value of diverse measures and high-quality RWE in informing healthcare decisionmaking [30,126]. When selecting effectiveness inputs for use in CEA, there is a need for practicality, to 'do the best with the available data', and to continue to prioritize analyses of patient-centric endpoints (e.g., hospitalization) in the real-world setting. For example, a Dutch study found that a major driver of cost savings with enhanced vaccines compared with standard vaccines in older adults was the prevention of cardiovascular-related hospital admissions [103], a real-world endpoint that may not be practical to study in a RCT setting. Furthermore, the practical real-time use of RWE has been demonstrated during the coronavirus disease 2019 (COVID-19) pandemic, a setting in which rapid policy decisions were required to save lives [120,127,128]. RWE aided the characterization of COVID-19 natural history, symptoms, and identification of clinical features associated with increased disease severity [127,128]. Real-world data provided confidence in the effectiveness and safety of COVID-19 vaccination in special populations, such as pregnant women, who were excluded from vaccine clinical trials [129]. Although the authors pointed out that most of the RWE reviewed had some risk of bias, the available data were sufficient to be highly reassuring to patients and providers who had to make decisions based on available data at the time [129].
With increased influenza rates in 2022-2023 compared with pandemic years [130], and risk of co-infection with influenza in patients with COVID-19 [131], there is a clear need to prevent extra hospitalizations to maintain hospital bed capacity; adequate protection of older individuals from influenza with enhanced vaccines supports this goal.

Importance of RWE Meta-Analysis
Although several systematic reviews of enhanced vaccines support the comparable effectiveness of aTIV/aQIV and HD-TIV/HD-QIV for older adults [11,92,132], in the absence of RCT data and head-to-head comparisons between enhanced vaccines, different approaches to model assumptions and evidence strength grading may explain some variation in CEA findings across studies and industry sponsors. The European Centre for Disease Prevention and Control (ECDC) 2020 technical report on the efficacy, effectiveness, and safety of newer and enhanced seasonal influenza vaccines determined that the evidence base for the efficacy/effectiveness of enhanced influenza vaccines is 'limited' and comparability of enhanced vaccines with traditional seasonal influenza vaccines is 'uncertain' because of a lack of literature and because of clinical and statistical heterogeneity [133]. In the report, using GRADE criteria, relative efficacy data with HD-TIV versus TIV from one RCT (rVE 24.2%) and relative efficacy data with QIVr versus QIV from another RCT (rVE 30%) were classified as moderate-strength evidence. Conversely, VE data from five observational studies across three seasons (2011)(2012)(2017)(2018), and 2018-2019; VE 44.9%) were graded as low-strength evidence, because the data were generated from non-randomized sources and subject to risk of bias and imprecision [133]. In this context, different rVE estimates have been used by different researchers in CEA to model the economic benefits of aTIV/aQIV compared with other options (Figures 1 and 2).
Other systematic reviews highlight the limitations of available RCTs that evaluate enhanced vaccines [134] and the potential value in using rVE estimates from RWE (as well as from RCTs) for HD-TIV [135]. After publication of the ECDC report, Gärtner et al., 2022 found similar effectiveness between aTIV and HD-TIV in seven RWE studies, whereas aTIV was more effective than HD-TIV in three studies [11]. From a policy perspective, countries considering RWE when making vaccine recommendations have recommended aTIV/aQIV, alongside other enhanced vaccines, such as HD-TIV/HD-QIV, in individuals ≥ 65 years of age [18][19][20].
Best-available estimates of rVE may include those arising from systematic reviews, meta-analysis, and network meta-analyses [31], which enable comparison of three or more interventions simultaneously [136,137]. Meta-analyses of real-world data may provide more robust estimates of effectiveness based on pooled sources of evidence compared with those provided by single studies. Among composite studies of enhanced vaccines in older adults, meta-analyses by Domnich et al., 2022 andColeman et al., 2021 showed that aTIV and HD-TIV provide comparable effectiveness, which is supported by the Gärtner et al., 2022 systematic review; Lee et al., 2021 showed that HD-TIV is more effective than TIV [11,92,132,135]. These analyses were performed across large patient populations with data from multiple influenza seasons. rVE estimates from meta-analysis sources have been used in several CEA models assessing enhanced vaccines ( Figure 1) [57][58][59][60][62][63][64], and some studies have produced novel meta-analysis estimates for use as part of a CEA [60,64].
When head-to-head trials are not available and comparisons are needed across multiple vaccines, network meta-analysis (also known as mixed treatment comparisons or multiple treatments meta-analysis) is an additional methodological option that enables the effectiveness of three or more vaccines to be compared in a single statistical analysis to aid decision-making [136,137]. Existing studies of rVE between vaccine pairs are organized into a network linked by direct and indirect comparisons [136,137]. This approach enables comparative ranking between vaccines and, similar to traditional meta-analysis methods, may produce a more precise estimate of relative effectiveness than that estimated from single studies [136,137]. The utility of network meta-analyses to assess relative effectiveness has also been established for COVID-19 vaccines [138,139]; one network meta-analysis analyzing the relative effectiveness and safety of approved seasonal influenza vaccines in different age and patient risk groups has been published [140].

Limitations of Currently Available Influenza RCT Evidence
The HD-TIV versus TIV rVE point estimate from the FIM12 RCT is used consistently in CEA of HD-TIV (Figures 1 and 2). Although an important and well-designed study, the use of a single rVE estimate across multiple CEA may not reflect the reality of influenza, of which VE estimates may change seasonally because of virus mutations [32]. Use of the same efficacy or effectiveness data in multiple CEA may also over-represent a limited evidence base [32]. Variation in VE reflects the reality of changing vaccine performance across seasons and emphasizes the importance of continuous and current effectiveness data collection to underpin influenza vaccine policy.
A systematic review and meta-analysis of high-dose versus standard-dose influenza vaccine RCTs in adults ≥ 65 years of age illustrated the importance of understanding vaccine effects on influenza-associated hospitalizations and deaths, and these outcomes cannot be assessed from the high-dose influenza vaccine RCT evidence base [134]. Data from immunocompromised individuals were also lacking [134]; exclusion of high-risk populations has been identified as a general limitation of influenza vaccine RCTs [141]. The authors concluded that, even with RCT data comparing HD-TIV versus TIV, there is limited evidence confirming a reduction in LCI cases with HD-TIV, and limited evidence regarding clinically relevant outcomes [134]. The authors stated that longer-term pragmatic trials are needed to demonstrate impact in real-world settings [134].
More broadly, the limitations of RCT evidence have been highlighted by the pressing need for current evidence describing real-world endpoints during the COVID-19 pandemic [120]. RCTs may have practical, ethical, and timeline concerns; meta-analyses may also be affected by the inclusion of flawed individual RCTs that require subjective assessment of certain methodologies of constituent studies [120]. Conceptual proposals, such as next-generation evidence-based medicine (EBM), or EBM plus (EBM+), contend that taking a broader approach to defining clinically actionable evidence is necessary in certain situations, such as when information is needed for rapid and urgent decisionmaking [120,142]. Research groups have proposed new frameworks for evidence appraisal using interdisciplinary, pluralistic, patient-centric, and/or complex system paradigms to complement traditional hierarchical study design-driven approaches [120,142]. The COVID-19 pandemic has taught us that even without RCT evidence 'we cannot do nothing' [143].

Vaccine Acquisition Price
In CEA in which rVE estimates for aTIV/aQIV and HD-TIV/HD-QIV are comparable, vaccine acquisition price can be the major driver of CE estimates (Table 3). However, determining the price paid for vaccines is challenging, because vaccines are purchased from manufacturers with pricing subject to proprietary negotiation and rebates; some studies use adjustment methods to estimate vaccine acquisition and administration costs [62,144,145]. Furthermore, specific vaccine prices, or type of price (e.g., list, reimbursed price, etc.) are not always disclosed in CEA, which prevents robust comparative assessment.

Sensitivity/Scenario Analyses
Best practices in CEA call for interrogating model inputs and assumptions through one-way, multivariate, and probabilistic sensitivity and scenario analyses [30,146]. Varying model assumptions in a one-way or multivariate manner assists in identifying which parameters drive ICERs; these are often illustrated within tornado plots. Estimates from composite probabilistic sensitivity findings indicate how often ICERs may sit within willingness-to-pay thresholds; for example, when multiple parameters are randomly varied simultaneously across pre-set ranges, often illustrated on a cost-effectiveness plane. As public health authorities make recommendations that often remain in place for years before re-appraisal, decision-making incorporating assessment of the most extreme scenarios from CEA is of sound public interest. Furthermore, for infectious disease modeling, such as influenza, more methodologically complex dynamic models are valuable [31] because they are able to incorporate varying disease state disutility inputs, the likelihood of transition between different disease states, and the likely duration of disease states for a hypothetical cohort of individuals.
Many CEA of enhanced influenza vaccines account for aspects of parameter uncertainty (e.g., variance of rVE), although measures taken to assess methodological uncertainty (e.g., discount rates and time horizon) and structural certainty (e.g., static or dynamic models) were more difficult to assess. rVE is often varied in sensitivity/scenario analyses and identified as a key driver influencing cost-effectiveness estimates. Other CEA vary parameters not limited to vaccine coverage rate, VE at baseline, hospitalization rates, case fatality rates, outpatient complications, baseline utility, vaccine acquisition price, human capital costs, and discount rates for costs and/or outcomes.

Interpretation of ICERs
It is difficult to compare ICERs across studies, particularly from analyses performed in different markets/countries; however, aTIV/aQIV and HD-TIV/HD-QIV are estimated as consistently cost-effective compared with TIV/QIV across countries (Tables 2 and 3). Between CEA studies, estimated ICER estimates may differ. Not overlooking variations between markets, including differences in vaccines prices, costs of disease management, and opportunity costs, current thinking is that variations in ICERs are generally determined by two core drivers: vaccine acquisition price and rVE. From a practical perspective, despite differences in the rVE inputted into models, comparable rVE has been seen between enhanced vaccines from RWE [11,92,132]; thus, the fundamental driver of ICER differences may be vaccine acquisition price. Currently, adjuvanted vaccines are often priced less than high-dose vaccines.

Future Directions
As novel vaccine technologies become available, including nucleoside-modified messenger RNA vaccines [147], RWE-driven CEA for comparative assessment may become even more important. 'Big data' may be a valuable source of RWE as datasets become more analyzable, particularly when these data allow for alignment with patient-centric EMB+ approaches [120,142]. RCTs will not be replaced, but there is a need to rely more on RWE obtained from high-quality studies; as such, developing frameworks to define and/or rank RWE may have merit [29].
The continuous development of CEA models that account for the uncertainty of influenza in future seasons relies on updated RWE and robust use of sensitivity analyses. Effectiveness values from across multiple seasons allow for policymakers to consider more realistic and representative estimates accrued over time. In traditional evidence hierarchies, RWE may be graded as lower strength than RCT data because retrospective and observational studies contain bias [120]; however, RWE is particularly important to assess for influenza. Recent lessons from COVID-19 pandemic responses have illustrated how RWE can guide rapid public health action [120]. Network meta-analyses, especially those with value-of-information analysis, may become best practice sources for effectiveness inputs. Increased understanding of methods to control bias in real-world studies, and frameworks to enhance transparency in RWE publications, may make RWE an increasingly more acceptable contributing data source for vaccine policymakers.
Influenza B, a more genetically stable virus than influenza A, becomes the predominant strain compared with influenza A approximately every 4-5 years and is generally perceived to lead to milder disease than influenza A [148]. Outcomes data have challenged this perception, with some studies finding similar or excess mortality associated with influenza B as compared with influenza A [148]. QIVs that protect against influenza B have achieved lower effectiveness rates than anticipated, suggesting that more study of influenza B is required [148]. Future RWE studies may support preparedness against future changes in the relative prevalence and impact of influenza A and B.
Secondary bacterial infections may account for a substantial proportion of influenzarelated mortality during pandemics [149]. The most common co-infection pathogens include Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes, and Haemophilus influenzae [149]. The impact of influenza vaccination against secondary bacterial infections, or even in full, has not been widely studied clinically, but evidence suggests a protective effect against mortality outcomes related to invasive secondary disease [149]. Devising methods to identify and capture the value of potential protection against invasive bacterial disease within influenza vaccine CEA may allow for a more accurate representation of the value of influenza vaccines.

Conclusions
Across many studies, aTIV/aQIV and HD-TIV/HD-QIV demonstrate cost-effectiveness against TIV/QIV, despite diversity in model type, vaccine acquisition price, rVE estimate, and study perspective in individuals ≥ 65 years of age. aTIV demonstrates similar rVE compared with other enhanced vaccines across multiple influenza-related outcomes in older adults based on RWE.
Despite the bias inherent in their design, RWE studies provide crucial information needed in CEA. Sensitivity analyses within CEA are important to identify which parameters present greatest uncertainty, while probabilistic sensitivity analyses can provide an overall view of the robustness of output estimates. Well-constructed meta-analyses may reduce uncertainty regarding individual rVE point estimates and provide the best estimates of rVE. Although many variables are included in influenza vaccine CEA, rVE and vaccine acquisition price are key drivers of ICERs. In most markets, adjuvanted vaccines are priced lower than high-dose vaccines.
Overall, data from RWE and CEA provide clinical and economic rationales for the use of enhanced vaccines, such as aTIV/aQIV, in people ≥ 65 years of age. In addition to price considerations, countries that consider RWE when making vaccine recommendations have preferentially recommended aTIV/aQIV, HD-TIV/HD-QIV, and/or QIVr, in individuals ≥ 65 years of age [18][19][20][21][22].
Author Contributions: All authors made substantial contributions to the conception, analysis, and interpretation of literature review findings; critically reviewed draft manuscripts for important intellectual content and provided input into draft manuscripts; and provided final approval of the version to be published. All authors have read and agreed to the published version of the manuscript.